A widely accepted theory regarding the function of the prefrontal cortex is that it serves as a store of short-term memory. This idea was first formulated by Jacobsen, who reported in 1935 that damage to the primate prefrontal cortex caused short-term memory deficits. Karl Pribram and colleagues (1952) identified the part of the prefrontal cortex responsible for this deficit as area 46, also known as the dorsolateral prefrontal cortex (PFdl). More recently, Goldman-Rakic and colleagues (1993) evoked short-term memory loss in localized regions of space by temporary inactivation of portions of the PFdl. Once the concept of working memory (see also Working Memory Model) was established in contemporary neuroscience by Baddeley (1986), these neuropsychological findings contributed to the theory that the prefrontal cortex implements working memory and, in some extreme formulations, only working memory. In the 1990s this theory developed a wide following, and it became the predominant theory of PF function, especially for nonhuman primates. The concept of working memory used by proponents of this theory focused mostly on the short-term maintenance of information, and rather less on the manipulation or monitoring of such information or on the use of that information for decisions. Consistent with the idea that the prefrontal cortex functions predominantly in maintenance memory, delay-period activity in the PF has often been interpreted as a memory trace. (The phrase "delay-period activity" applies to neuronal activity that follows the transient presentation of an instruction cue and persists until a subsequent “go” or “trigger” signal.)

NIMH researchers Mikhail Lebedev, Adam Messinger, Jerald Kralik and Steven Wise challenged the working memory theory of prefrontal cortex function in the paper that they published in PLoS Biology (Lebedev, M.A., Messinger, A., Kralik, J.D., Wise, S.P. (2004) Representation of attended versus remembered locations in prefrontal cortex. PLoS Biology, 2: 1919-1935.) To explore alternative interpretations of delay-period activity in the prefrontal cortex, they investigated the discharge rates of single prefrontal neurons as monkeys attended to a stimulus marking one location while remembering a different, unmarked location. Both locations served as potential targets of a saccadic eye movement. Although the task made intensive demands on short-term memory, the largest proportion of prefrontal neurons represented attended locations, not remembered ones. These findings showed that short-term memory functions cannot account for all, or even most, delay-period activity in the part of the prefrontal cortex explored. The authors suggested that prefrontal activity during the delay-period contributes more to the process of attentional selection (and selective attention) than to memory storage.